ZDRAV VESTN 2002; 71: III-73–6 III-73

LARYNGEAL PAPILLOMATOSIS PAPILOMATOZA GRLA

Irena Hočevar Boltežar, Miha Žargi University Department of and Cervicofacial Surgery, Clinical Center, Zaloška cesta 2, 1525 Ljubljana, Slovenia

Arrived 2002-09-13, accepted 2002-10-15; ZDRAV VESTN 2002; 71: Suppl. III: 73–6

Key words: ; ; etiology; treatment Ključne besede: grlo; papilomi; etiologija; zdravljenje

Abstract – Background. Laryngeal papillomatosis is a rare Izvleček – Izhodišča. Papilomatoza grla je relativno redka disease of the upper , which may have a dra- bolezen zgornje dihalne poti, katere klinični potek pa je lahko matic course. The results of many studies have proved a viral za bolnika usoden. Številne raziskave so potrdile virusno etio- etiology, but the precise mode of the transmission remains logijo bolezni, ni pa še povsem pojasnjen prenos povzročite- indistinct. Surgery is the most successful mode of treatment. lja. Doslej najbolj uspešno zdravljenje je kirurško, za adju- Adjuvant therapy is indicated only in an aggressive form of vantno zdravljenje pa se odločamo samo v primerih agresivne the disease. oblike bolezni.

Patients. In the last 23 years, 136 patients have been treated Prikaz bolnikov. V zadnjih 23 letih se je na Kliniki za otorino- for laryngeal papillomatosis at the Department of Otorhino- laringologijo in cervikofacialno kirurgijo v Ljubljani zdravilo and Cervicofacial Surgery in Ljubljana. All pa- 136 bolnikov s papilomatozo grla. Vsi so bili zdravljeni kirur- tients were treated surgically; since 1995, CO2 laser has been ško, od leta 1995 dalje s pomočjo laserja CO2. 18 bolnikov z used. Eighteen patients with aggressive disease received adju- agresivno obliko bolezni smo zdravili še z adjuvantno terapi- vant therapy. Only in 2.2% of patients was nece- jo. Le pri 2,2% bolnikov je bila potrebna traheotomija zaradi ssary. In 9.6% of patients, laryngeal scarring occurred as a ogrožene dihalne poti. Pri 9,6% bolnikov so nastale brazgotin- result of repeated surgical procedures. In 2.2%, malignant al- ske spremembe v grlu kot posledica ponavljajočih kirurških teration of laryngeal papillomatosis developed. posegov. Pri 2,2% bolnikov se je v grlu nekaj let po vzniku papilomov pojavil karcinom. Conclusions. The outcome of treatment of laryngeal papillo- matosis in Ljubljana is comparable to the results of other cen- Zaključki. Uspehi zdravljenja bolnikov s papilomatozo grla v tres. As may develop, although very rarely, more Ljubljani so primerljivi rezultatom drugih svetovnih centrov. than 10 years after the onset of laryngeal papillomatosis, all Zaradi možnega – čeprav redkega – pojava ploščatocelične- patients must be followed carefully. ga karcinoma v grlu tudi več 10 let po pojavu papilomatoze grla, je nujno stalno dolgoletno spremljanje bolnikov.

Etiology onset LP, infection occurs in childhood and activates when the immune defence is affected. Vambutas et al. postulated Laryngeal papillomatosis (LP) is a relatively but is that there may exist a defect in the normal T cell-mediated still the most common pediatric found in the larynx host response that allows progression to active disease (10). (1). The etiology of the disease is the human virus Snowdon et al. detected significantly lower levels of interleu- (HPV). The most common types of the virus that have been kin-2 and IL-2 receptor in patients with recurrent respiratory identified are HPV types 6 and 11 (2, 3). Other less common papillomatosis compared with normal children. These data presenting types include types 16 and 18; these have been support the presence of an aberrant cell-mediated immune associated more closely with malignant transformation (4, 5). response in children with LP (11). HPV is a small, DNA-containing, non-enveloped capsid virus with a double-stranded DNA that is 7900 base pairs long (6). According to current theory, HPV enters the basal layer cells Epidemiology of traumatized epithelia. HPV DNA amplification then takes place, mostly in the upper epithelial cell layers (7). LP is recognized as a disease of both children and adults. The Some studies have established an association between cervi- incidence among children in the United States is estimated at cal HPV infection in the mother and the incidence of LP in the 4.3 per 100, 000 children – meaning around 2400 new cases child (8). There is an increased risk of developing LP for the every year (12). For patients in Denmark, the incidence is 3.84 first-born, vaginally delivered child of a teen-age mother. In per 100, 000 per year. The rate among children is 3.62 per 100, cases of neonatal LP, development of the disease may occur 000, whereas adult-onset cases occur at a rate 3.94 per 100, 000 in utero. In adult-onset LP, HPV can be sexually transmitted. (13). Patients with LP have significantly more sex partners over the Lindeberg et al. classified LP into juvenile and adult forms (14). course of a lifetime and a higher frequency of than The juvenile form is most often diagnosed between 3.3 and 4 non-affected adult controls (9). It is also possible that in adult- years of age. Distribution among boys and girls is approxi- III-74 ZDRAV VESTN 2002; 71: SUPPL III mately equal. The adult form peaks in the third decade of life with the aim of providing optimum relief of symptoms while and has a male predilection (15, 16). preserving essential anatomy and function. The CO2 laser has In the last decade, a classification replacing the terms »juve- been favoured over cold instruments in the treatment of LP nile« and »adult« with »aggressive« and »non-aggressive« was because it vaporizes the lesions and causes minimal bleeding. proposed by Doyle et al. and is probably more appropriate Using the appropriate technique, the damage to vocal folds for clinical use. LP is defined as being aggressive in patients is small and scarring is limited The risk of anterior glottic requiring a total of 10 or more procedures, and 3 or more webbing, interarytenoid scarring, and vocal fold fibrosis in- procedures over a 1-year period, or spread to the subglottic creases with the number of operative procedures (32). In a region (15). It is believed that the aggressive form of the di- study by Perkins et al. of 50 patients with juvenile-onset papillo- sease is associated with infection with HPV 11 (17, 18). matosis, 7 patients (14%) developed airway stenosis (33). To decrease the risk of scar formation in the vocal folds, cold steel phonomicrosurgical excision with submucosal infusion Clinical course can be used. This approach may even have advantages over

The characteristic of LP in children is the triad of progressive CO2 laser (34). hoarseness, and respiratory distress. The symptoms Recent reports on new surgical techniques have highlighted can range from a weak cry to complete aphonia, chronic cough, their potential benefits. The 585-nm pulsed dye laser can cause paroxysms of choking, recurrent respiratory infections, com- regression of papillomas, causing selective destruction of tu- promised airway, cyanosis or failure to thrive. In mor microvasculature with preservation of the epithelial sur- adult patients, hoarseness is the most common symptom (16, face, avoiding damage to the underlying tissue (35). Argon- 19, 20). plasma coagulation of the papillomas in the larynx has the The papilloma appears as an exophytic, branching, peduncu- advantages of controlled limited penetration into the tissue lated or sessile mass, single or multiple, most frequently loca- and good control of bleeding (36). ted on vocal folds, ventricular folds, the subglottis and laryn- The KTP laser’s primary advantage is that it uses a fiber, which geal surface of the epiglottis (3, 21). Histologically, papillomas can be passed through the bronchoscope to reach tracheal appear as fingerlike projections of stratified squamous epi- and bronchial papillomas with relative ease (37). Outcomes thelium with a fibrovascular core. Basal cell hyperplasia and are virtually the same as with CO2 laser for LP. Currently, some large vacuolated epithelial cells with a clear cytoplasm (koilo- authors recommend a laryngeal micro resector system deve- cytosis) are typical (3, 22, 23). loped from powered instrumentation for sinus surgery. It is While LP is initially diagnosed mostly at a glottic level, papillo- suitable for rapid elimination of laryngeal papillomas (37, 38). mas may spread to any location along the respiratory tract. In In patients with massive disease and compromised airway, more than half of the juvenile-onset LP, the subglottis is in- tracheotomy is necessary. The frequency of tracheotomy in volved (15). However, pulmonary spread occurs in only 0.8% patients with the juvenile-onset form of the disease has ranged of all children (24). Some authors suggest that tracheotomy from 11% to 60% (14, 23, 24). performed because of massive LP may activate or spread the disease lower in the respiratory tract (25). Adjuvant treatment modalities Although spontaneous remission is reported, its occurrence is highly variable and unpredictable. The reasons can be en- About 10% of patients with LP require some form of adjuvant docrine, immunologic, or hormonal factors, although the pro- therapy. The most widely adopted criteria for initiating adju- posed association between remission and the onset of puber- vant therapy are a requirement of more than four surgical ty is debatable (15, 26). procedures per year, distal multisite spread of the disease, and/ An approximately equal percentage of children (17%) and or rapid growth of papillomas with airway compromise (19). adults (19%) have the aggressive form of the disease (12). There Many alternative or adjuvant treatment modalities have been may be a relationship between prognosis and even death and abandoned because they failed to demonstrate reproducible the age at which initial symptoms occur (15, 27). Chipps et al. benefits. They include ultrasonography, cryosurgery, steroids, reported that all patients developing symptoms within the first podophyllum, estrogen, suction diathermy, transfer factor, 6 months of life died from their disease (28). lymphokines, levamisole, antibiotics, and irradiation It is believed that the aggressive form of the disease is associ- (15). Several newer forms of adjuvant therapy have shown ated with infection with HPV 11 (17, 18). The results of a study promising results in improving the control of LP, although by Pou et al. suggest that HPV 11 and 16 are associated with none seem able to eradicate the HPV genome from laryngeal the aggressive disease. Coinfection with additional , mucosal tissue. These include , antiviral drugs such particularly virus, appears to predispose in- as acyclovir, , and , indole-3-carbinole, isotre- fected individuals to a more aggressive disease (29). tinoin, and . The incidence of malignant transformation of LP is reported Alfa- has been the most extensively investigated to be from 0% to 10.3%. Most occurrences have been reported form of adjuvant therapy. It modulates the host immune re- in adult patients and are associated with other risk factors, sponse and induces complete resolution of clinical disease in such as smoking, or prior irradiation; however, malignant trans- approximately 30% to 50% of patients and partial resolution formation also occurs in children. In adults, invasive carcino- in 20% to 42% (39, 40). Interferon has many side-effects so it is mas usually arise in the larynx. In children, usually de- only recommended in the aggressive form of the disease. A velops in the bronchopulmonary tree, including the . In major concern in its use is a rebound effect after its discontin- patients who had been irradiated for their juvenile-onset LP, uation. The rate of recurrence may approach 50%. Most of the incidence of malignant transformation is reported to be these patients respond to another course of therapy (40, 41). 14% (4, 15, 28–31). Walther and Herberhold have reported on success in all nine patients treated with interstitial alpha-interferon injections into the laser surgical coagulation area following laser excision of Treatment modalities papillomas (42). Acyclovir inhibits DNA replication of the human herpes sim- Surgical management plex virus. Acyclovir is not directly effective against HPV, but No single modality has been shown to be effective in eradica- is presumed that augments HPV replica- tion of LP. The current standard treatment is surgical therapy tion. Since coinfection with herpes simplex virus has been HOČEVAR-BOLTEŽAR I, ŽARGI M. LARYNGEAL PAPILLOMATOSIS III-75 found in 50% of patients with LP, it is possible that inhibition In 56 patients (4 patients with JLP, 52 patients with ALP), only of the herpes simplex virus may indirectly slow the growth of one procedure with microsurgical resection of the papillo- HPV (29, 43). Kiroglu et al. detected complete resolution of LP mas was necessary. At their last check-up, the patients had no in 9 of 12 patients who had been treated with acyclovir after papillomas in the larynx. In 65 patients, from 2 to 9 proce- surgical ablation of papillomas (44). dures were performed. In 15 patients (11 patients with JLP, 4 Ribavirin is an , which is used to treat respirato- patients with ALP) a total of 10 or more surgical procedures ry syncytial virus . In children treated with ribavi- were necessary. rin the interval between the necessary surgical procedures Twenty-seven patients with JLP required 265 procedures, with increased (45). an average of 9.8 procedures per patient. In 109 patients with In two recent studies cidofovir, a drug approved for patients ALP, 263 surgical procedures were done with an average of with HIV having -retinitis, was injected directly 2.4 procedures per patient. into the papilloma bed after laser surgery (46, 47). Snoeck et One patients was irradiated because of LP in his childhood. al. noted a complete response in 14 out of 17 patients (46). Eighteen patients were treated with adjuvant therapy. The Recent interest has focused on chemically pure indole-3-car- adjuvant therapy was started in those patients who required 3 binol, which has been shown to inhibit papilloma formation or more surgical procedures per year, and in two other pa- in mice. Newfield et al. found that HPV-infected laryngeal ti- tients with massive disease. ssue metabolizes estradiol into 16a-hydroxyestrone, a tumori- One child received interferon one year before being treated genic metabolite, at a higher level than normal tissue. Indole- at our Department in Ljubljana. After cessation of adjuvant 3-carbinol inhibits the hydroxylation of estradiol to 16a-hy- therapy, a massive relapse of LP occurred and required laser droxyestrone (48). Rosen et al. reported preliminary results in treatment. 18 children who were treated with this drug, with 6 patients Four children were treated with an autovaccine. Three patients showing a complete response, 6 a partial response, and 6 no required several microsurgical procedures after being trea- response (49). ted with . In one to four years after the treatment with Positive results of treatment with isotretinoin, a vitamin A de- vaccine, LP disappeared and they have had no evidence of the rivative, have been rarely reported (50). A randomized study disease for the last 7, 8 and 13 years respectively. One boy had failed to demonstrate any efficacy and found a high incidence no laryngeal papillomas but still persisting papillomas in the of annoying side effects (51). after treatment with the vaccine. Photodynamic therapy is based on the transfer of energy to a Two children and seven adults were treated with acyclovir. photograph-sensitive drug (dihematoporphyrin ether), which Five of them had no evidence of disease after microsurgical or has a tendency to concentrate within papillomas. The photo- laser ablation of the papillomas and an eight-week course of activation is delivered by argon-pumped dye laser and tissues acyclovir. In two patients, the period between two surgical with high concentration of the drug are destroyed. The treat- procedures was prolonged. In one patient the treatment had ment is not curative, but it is reported to reduce notably the no success. growth of papillomas (52). Three children were given indole-3-carbinol. In all three pa- tients, the period between two surgical procedures was pro- longed from three months up to twelve months. Our patients All patients were followed-up from 0.5 month to 22 years, mean 30.4 months. At their last visit, in 113 patients (21 patients with A total of 139 patients with a diagnosis of LP were treated at JLP, 98 patients with ALP) there was no evidence of LP, in 13 the Department of Otorhinolaryngology and Cervicofacial patients (5 patients with JLP, 8 patients with ALP) a recurrent Surgery in Ljubljana from 1979 to 2002. In three patients, inva- LP was established. One patient died because of suffocation sive laryngeal squamous carcinoma occurred 3 to 7 months with papillomas. In 3 patients with ALP (2.2% of all patients after finding papillomas in the larynx; and they were there- with LP) laryngeal carcinoma occurred 2, 4 and 5 years after fore excluded from the series. the last microsurgical procedure for LP. Six subjects were lost Of the 136 patients with LP, 95 were male and 41 were female. from follow-up. In 27 patients, LP occurred before they were 15 years of age In 13 subjects (9.6%), 9 subjects with JLP, and 4 subjects with (juvenile-onset form). At the disease onset they were from 1 to ALP, there were scars in the larynx but they did not compro- 12 years of age, mean 5.8 years. There were 13 boys and 14 mise the airway. All three patients who had had a tracheotomy girls in the group with juvenile-onset LP (JLP). in their childhood, had no papillomas in the larynx and the Of the 109 patients with adult-onset LP (ALP), 82 were male stoma was closed. and 27 were female. LP occurred when they were from 16 to 82 years of age, mean 46.1 years. Aggressive disease In 73 patients (5 patients with JLP, 68 patients with ALP) pa- pillomas occurred in the glottis. In 28 patients (2 with JLP, 26 According to Doyle et al., LP was defined as being aggressive with ALP) the disease spread over the glottic and/or supraglot- in patients requiring a total of 10 or more procedures and 3 or tic region. Thirty-five patients (20 with JLP, 15 with ALP) devel- more procedures over a one year period or subglottic spread oped subglottic papillomas during their course of disease. during the first 6 months of the disease process (15). Using Neither spread of the papillomas in the tracheobronchial tree these criteria, 16 of our patients had aggressive disease (12 nor pulmonal spread was found in any of the patients. subjects with JLP, 4 subjects with ALP). Among subjects with aggressive disease, there were 8 girls, 4 boys, 3 men and 1 Treatment woman. In 136 patients, 528 surgical procedures were required. Forty- five procedures were performed in 13 patients before the year Conclusions 1979 or in other hospitals. In 23 years, 366 microsurgical and 117 laser procedures were performed at the University Depart- In the last 23 years, 136 patients with LP were treated at the ment of Otorhinolaryngology and Cervicofacial Surgery in University Department of Otorhinolaryngology and Cervico- Ljubljana. Laser was used for evaporation of papillomas after facial Surgery in Ljubljana. The demographic characteristics the year 1995. In three patients, tracheotomy was necessary of the patients, the localization of the disease, the mode of because of respiratory distress in their childhood (before 1979). treatment, and the outcome of treatment are about the same III-76 ZDRAV VESTN 2002; 71: SUPPL III as reported in other series. In comparison with other reports, 26. Mahnke CG, Werner JA, Frölich O, Lippert BM, Hoffman M, Rudert HH. only in 9.6% of patients laryngeal scarring occurred as a result Klinische und molekularbiologische Untersuchungen zur laryngalen Pap- illomatose. 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